The human nuclear receptor family consists of 48 transcription factors that mostly utilize hydrophobic ligands to regulate their activities. These proteins each consist of a series of discrete segments, which include an A/B region, a DNA binding domain (DBD), a hinge segment, a ligand binding domain (LBD) and in some cases additional regions. A series of informative crystallographic studies carried out to date have provided important insights into nuclear receptor DBD and LBD structures and functions, but only as isolated domains. There is no structural understanding of intact nuclear receptors that would show how their different regions are wired together to coordinate their complex functions. Aim 1 of the proposal is directed at providing the detailed structural and dynamic properties of the heterodimeric complex involving full-length RXR-alpha/PPAR-gamma proteins in complex with their ligands and assembled on their DNA target site. The other aims of the proposal are directed at another limitation in the nuclear receptor field related to the "orphan" members - whose ligands remain unknown. Nearly half of all the nuclear receptors in humans have remained orphans, decades after their initial cloning and sequencing. Due to the lack of ligand tools to modulate their activities, the functions of these receptors in regulating genes and biological pathways have remained largely unclear. We propose to study the two orphan nuclear receptors most closely related in sequence to PPARs. We have found that these receptors, rev-erb alpha and rev-erb beta, use heme (iron-porphyrin IX) as their common ligand. We propose to study how heme regulates the activities of these receptors in a series of different contexts, and to visualize crystallographically how heme binds to their internal pockets to reshape their interactions with coregulators. The first objective of the proposal is directed at providing the detailed structural and dynamic properties of the complex of full-length RXR-alpha/PPAR-gamma proteins in complex with their ligands and assembled on their DNA target site. The RXR/PPAR complex is a validated drug target for type II diabetes. The second emphasis area is directed at characterizing the ligands, structures and functions of the orphan nuclear receptors: rev-erb alpha/beta which play important roles in psychiatric and metabolic diseases.